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Reviewed by
John K. Fink,
M.D.,
SPF Medical Advisor
A hereditary or genetic disorder is
caused by a change (mutation) in a gene. Genes are
pieces of biochemical information that form the
instructions (code) for the thousands of proteins the
body uses to build itself and function. Half of
someone's genes come from their mother and half come
from their father. Some genes are responsible for
obvious traits such as eye color. Others control the
production of substances essential to bodily processes.
Some act as on-off switches for other genes.
When a gene is altered, the instructions cannot be coded to make
the correct protein. As a result, the protein might not be created at all, or
might be made incorrectly. While many gene mutations have little or no effect on
the body, some can result in the development of serious genetic disorders. In
HSP, gene mutations alter the code for proteins involving particular nerve cells
in the brain and spinal cord, which disrupts their proper functioning.
The mutated gene that causes HSP can be passed down from parent
to child. However, inheriting a mutant HSP gene does not automatically mean
someone will have the disorder. There are many forms of HSP, each caused by
different genes. The risk of inheriting the disease depends on the particular
features of the gene involved.
Answers to specific questions can be found
below. In addition to reading over the information below, you can also find
information at:
Humans have about 50,000 genes. Genes come in pairs,
and each pair makes up a very small section on a
chromosome. Humans have 46 chromosomes arranged in 23
pairs in every cell in the body, except for the sperm
and egg cells.
Twenty-two of these pairs are called autosomes and they are the same for
each sex. The twenty-third pair of chromosomes consists of the sex chromosomes.
Women have two X chromosomes while men have one X and one Y chromosome. The Y
chromosome determines maleness.
Sperm and egg cells contain just one of the chromosomes from each pair,
i.e., 23 individual chromosomes. When a sperm and egg come together and
conception begins, a new cell is formed that brings the individual chromosomes
together into one pair. Thus, every person receives half of his or her genes
from the father’s sperm cell, and half from the mother’s the egg cell.
HSP is not one disease but rather a group of similar
disorders, each caused by different genes that cause
very similar symptoms. The risk of inheriting an HSP
disorder depends on the particular features of the gene
involved. In other words, it depends on whether the gene
lies on an autosome or the X-chromosome, and on whether
the gene is dominant or recessive. In some forms of HSP,
it can also depend on the sex of the child and/or the
parent.
There are three different modes of inheritance: autosomal dominant,
autosomal recessive, or X-linked.
- Autosomal dominant
Most forms of HSP are autosomal dominant. Autosomal means the HSP gene is
located on one of the autosomal chromosomes. The gene can be present in
either sex, and it can be passed down from either a mother or a father to a
son or a daughter. Dominant means that only one HSP gene is needed to cause
the disorder.
Since there is a 50% chance a child will receive the dominant HSP gene
mutation from the affected parent, there is a 50% chance the child will
inherit the gene and the disorder. This is the same risk for every birth,
independent of every other birth.
Note: There are many reasons why someone with no apparent family history may
have an autosomal dominant form of HSP. Please see “How can it be HSP when
no one else in the family has it?” below.
• Autosomal recessive
Some forms of HSP are autosomal recessive. This type of HSP also lies on one
of the autosomes, so it can be present in males or females and passed to
males or females. Since it is recessive, two copies of the gene are needed
to result in the disorder, one from each parent.
In these forms, neither parent has HSP. Instead, they are carriers. They
each have one mutant HSP gene and one normal HSP gene. A mutant HSP gene
that is recessive can be passed down silently for generations until someone
finally inherits the recessive gene from both parents and develops the
disorder.
If a mother and father are each carriers for a recessive HSP gene mutation,
each of their children has a 25% chance of developing HSP. This is the same
risk for every birth. There is a 50% risk the child will be a carrier like
the parents. That child would receive one mutant HSP gene from one parent
and a normal HSP gene from the other. There is a 25% chance that the child
would receive only the normal HSP genes from each parent. This child would
not be affected by HSP, nor would he be a carrier.
For individuals with autosomal recessive HSP to have children with the
disorder, their spouses have to either have the disorder or be a carrier.
This is possible in marriages between cousins in families with this type of
HSP.
• X-linked
Some HSP genes are found on the X chromosome. Disorders due to genes on the
X chromosome are called sex-linked or X-linked since the gene is on one of
the sex chromosomes.
The inheritance risks and severity of this type of HSP differ depending on
the individual’s sex. Women with an X-linked mutant HSP gene are generally
not affected by the disorder; or, if they are, usually have less severe
symptoms than males.
Each son of a woman who is a carrier for X-linked HSP has a 50% chance of
developing HSP. Each daughter of a woman who is a carrier for X-linked HSP
has a 50% chance of being a carrier (female carriers of X-linked disorders
often have no symptoms).
Special questions
How can it be HSP when no one else in
the family has it?
There are many explanations for why individuals who
have all the signs and symptoms of HSP do not appear to
have a family history of the disorder. The most common
reason is that the condition may be recessive or
X-linked. These forms may have passed down silently for
generations until the correct circumstances existed for
someone to have the disorder.
Even someone with a dominant form of HSP may not appear to have a family
history of the disorder. Since HSP can vary greatly in severity of symptoms and
age of onset, a parent may have had a very mild case. His or her symptoms may
have gone unnoticed or been attributed to other problems such as old age or
arthritis. In addition, since symptoms can develop later in life, the person may
have died before showing symptoms, or if still living, may not have developed
them yet. Finally, it could be a new gene mutation, making the affected person
the first in his family.
Will HSP have
an earlier onset and/or more severe symptoms in
subsequent generations?
While the
odds of any given conception having a gene mutation can
be calculated, it is not possible to predict how severe
symptoms will be or the exact age of onset. Hereditary
spastic paraplegia (HSP) has significant variation in the
degree of functional impairment (difficulty walking). The severity of symptoms
may vary both between different genetic types of HSP and also within one family
in which affected individuals not only have the same genetic type of HSP but
also have the exact same HSP gene mutation.
Sometimes, but certainly not always, symptoms begin at earlier ages and may be
more severer in subjects in succeeding generations. For example, symptoms may
begin in the grandparent at age 35, in the child at age 15, and
in the grandchild at age 5. This pattern, called "genetic anticipation" is
certainly not the rule, however.
Often, "genetic anticipation" can not be distinguished from "random chance".
Since the age at which symptoms begins is variable, it is possible that just by
random chance, members of a small family (such as only three affected subjects)
could appear to have this pattern of "progressively younger/genetic
anticipation" (when actually, it was just a random chance that the ages of
symptom onset fell into this pattern).
Therefore, since a) genetic anticipation is not always seen (indeed does not
appear in most families), and b) HSP symptom onset and severity are variable
even within families, and c) most families are too small to make statistically
significant predictions, we do not make predictions that HSP symptoms in
subsequent generations will definitely be more severe or begin earlier.
Do people with HSP experience memory
loss?
Memory
disturbance has been reported in some individuals with HSP due to spastin gene
mutations. In general, it was mild.
Before attributing memory disturbance to HSP, it is important to consider other
causes: stress, anxiety, depression, lack of sleep, medications (including
Baclofen), other health conditions including vitamin B12 deficiency.
If memory disturbance is significant, a cause of concern, or worsening, it would
be important to discuss this with your primary physician and neurologist.
What about genetic testing for HSP?
Athena Diagnostics currently offers testing for
HSP mutations in five different genes. The test is
called the Hereditary Spastic Paraplegia Evaluation.
Some insurance policies will cover some or all of
the fees while others will not cover the testing.
These five genes are responsible for approximately 70%
of dominantly inherited forms of HSP. Mutation in
one of these genes (for dominantly inherited HSP)
are also found in approximately 10% of individuals
who have progressive spastic paraplegia but no
previous family history. Researchers have identified
39 different genetic forms of HSP. Hopefully,
analysis for additional HSP genes will become
available and increase laboratory diagnosis of HSP.
Gene tests can also be used for prenatal testing.
Editor's Note: A member of our community submitted
an article on gene testing. Please see
Patient Forum - gene
testing.
In addition, the following website is mainly written for
health care providers but offers valuable
information for lay people as well -
http://www.genetests.org/
Are there risks associated with genetic
testing?
Having a small amount of blood drawn doesn’t hold
much risk, however, there are many important issues to
consider. Genetic testing is so new that the legal,
ethical, and medical implications are still unclear.
Genetic testing can potentially interfere with privacy,
insurance eligibility, or employment.
In addition, pre-symptomatic or carrier testing of children is highly
controversial. Many experts do not encourage testing at-risk children or
adolescents to determine whether they may eventually develop HSP. Some medical
centers prohibit genetic testing of minors unless there is a compelling medical
reason. Even testing of adults can have unintended consequences.
That’s why seeking guidance from a genetics counselor is a wise idea when
considering testing. Counselors may be medical professionals with special
training or individuals who have received education and certification as genetic
counselors. They provide information about inheritance and the chances of having
children affected by a particular inherited disease. They can also provide
emotional support and make referrals to appropriate resources.
Neurologists can refer interested individuals to genetics counselors. A good
online resource is the
National
Society for Genetic Counselors.
For lots of information on genetics, please visit the
National Institutes of
Genetics Home Reference, the MDA’s Web site
http://www.mdausa.org/publications/gen_inhr.html
and the Genetics Alliance
site
http://www.geneticalliance.org/ws_display.asp?filter=tools.
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